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OCR for page 301
APPENDIX J
IMMUNOLOGICAL CONSEQUENCES OF ANTIMICROBIALS IN ANIMAL FEEDS
N. Franklin Adkinson, Jr.1
This paper addresses the issue of whether antibiotic residues
consumed in edible animal tissues sensitize and/or elicit allergic
reactions in humans. Although many antibiotics are potentially
sensitizing in susceptible individuals, the focus of this paper is
upon the penicillins and tetracyclines. Of these, the penicillins
have far greater allergenic potential.
The allergenicity of penicillins has been studied extensively
(Levine, 1966; Stewart, 1973~. Because the penicillin group of
drugs is considered the prototype for allergic reactions to drugs
(Parker, 1975), much of the following commentary is derived from
knowledge of hypersensitivity to penicillin. The principles in-
volved, however, should apply to less allergenic antibiotics in-
cluding the tetracyclines and aminoglycosides.
There are three basic questions concerning this issue:
1. Is there a potential for allergic reactions in humans
either directly or indirectly attributable to antibiotics in food-
stuffs?
2. Are there documented cases of such allergic reactions to
antibiotic residues, and, if so, what is the magnitude of the pro-
blem?
3. What studies could be conducted to document further the
extent of the problem, both actual and potential?
PREVALENCE OF ALLERGIC SENSITIVITY TO PENICILLINS AND TETRACYCLINES
Penicillins display remarkably little toxicity even in high
doses. Most adverse reactions are attributed to "allergy."
Allergic reactions to penicillin range from anaphylactic shock,
which can be life-threatening and even fatal,-to mild evanescent
skin rashes of little clinical consequence. These allergic reac-
tions have differing immunological mechanisms (Table 1~. When
Division of Clinical Immunology, Department of Medicine, Johns
Hopkins University School of Medicine at the Good Samaritan
Hospital, Baltimore, Md.
301
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302
TABLE 1
Immunopathological Reactions to Penicillin
Gell and Examples of Adverse
Coombs Type Description Penicillin Reaction
I Anaphylact ic Acut e anaphylaxi s
· (IgE-mediated injury) Urticaria
II C '-dependent cytolysis Hemolytic anemias
Thrombocytopenia
Interstitial nephritis
III Immune complex damage Serum sicknes s
Drug feve r
Cutaneous erupt ion s
IV " Delayed " or c el lular Contac t de rmat iti s
hype rsens itivit
aImmunopathogenesis of cutaneous eruptions is not clear.
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303
penicillins are given in therapeut ic dose s, the inc idence of
severe life-threaten~ng reactions is small, probably less than
1 in 50,000 courses of treatment (Ids~e et al., 1968~. However,
because of the huge quantities of penicillin drugs administered
yearly in the United States, there are an estimated 300 to 500
deaths frog anaphylactic reactions to therapeutic penicillin
each year (Feinberg, 1961~. On the other hand, mild reactions
to penicillin, principally skin eruptions resembling those of
measles, are common, and, at least for one semisynthetic peni-
cillin (ampicillin), may afflict 10% to 12% of treated patients
(Almeyda and Levantine, 1972~.
Between 1% and 10% of the general population will relate
a history of some adverse experience associated with penicillin
therapy. The lower prevalence figure (1%) is probably more
applicable to children and young healthy adult s, while the higher
prevalence figure (10%) reflects the frequency with which medical
chart s are likely to be marked "allergic to penicillin" among
older patients hospitalized for serious medical problems. More
recent s tudies of the most serious forms of allergy to peniicillin
~ type I in Table 1: IgE-mediated, or reagenic, allergy) have shown
that some patients s pontaneously lose allergic sensitivity with
time (Adkinson et al., 1971; Green et al., 1977; Levine and Zolov,
1969~. This spontaneous loss of allergic sensitivity is likely to
occur for other less serious types of allergic reactions as well,
judging from the fact that it is often possible to treat previously
allergic individuals safely (Biennan et al., 1972 ; Levine, 1972 ~ .
Tetracyclines are infrequently implicated in allergic reac-
tions. Allergic reactions of the type I variety (anaphylactic
shock and urticaria) have occasionally been documented in the
literature (Schindel, 1965) but are extraordinarily rare. Tetra-
cycline-induced skin rashes, including phototoxic dermatitis, are
the most common adverse reactions that are generally considered
"allergic, " although there is no clear evidence of an immunologi-
cal basis for these reactions (Dewdney, 197 7 ~ .
CONI) IT IONS FOR SEN S ITIZAT ION
Some of the factors that influence the development of aller-
gic hypersensitivity to penicillin are: chemical structure and
reactivity of the drug; cross-reactivity with other sensitizers;
dosage, duration of therapy, number of courses of therapy; mode
of administration of the drug; use of additives and solvents; and
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304
patient factors, including history of drug sensitivity, atopy,
age, genetic factors controlling drug metabolism or immune re-
sponse, and underlying disease affecting metabolism of excretion
of the drug.
Three factors deserve mention in the present context: pro-
tein reactivity, individual susceptibility, and dose requirements.
Protein Reactivity
Drugs, like all small molecular weight chemicals, cannot
stimulate an immune response in animals or humans unless they
possess the capacity to "haptenize," i.e., interact irreversibly
with larger molecules, usually proteins, thereby forming an
immunogenic multivalent drug-protein complex. The immunochemistry
of such interactions between penicillin and native proteins has
been studied in detail (Stewart, 1967~. The principal pathways
involved are schematized in Figure 1.
The major antigenic determinant for penicillin is the peni-
cilloyl moiety of the complex, formed by covalent linkage of the
beta lactam ring of penicillin to epsilon amino groups of lysine
residues in native proteins. This antigenic complex is formed
naturally and spontaneously under physiological conditions without
known participation of enzymes or catalysts. This penicilloyl-
protein complex stimulates the host immune system to produce
antibodies and immunoreactive cells that are capable of inflicting
immunopathological damage. It is now well established that pre-
formed penicilloyl-protein complexes are much more efficient than
the unconjugated penicillin molecule at both stimulating an immune
response and eliciting an allergic reaction in a previously sensi-
tized individual (Siegel, 1959; Stewart, 1967~. Immunologically,
the antibiotic "residue" of prime importance is the penicilloyl-
protein complex rather than the free penicillin molecules. As is
discussed further below, no analyses of penicilloyl residues in
foodstuffs obtained from penicillin-treated animals have ever been
undertaken.
The relationship of the a topic status to various types of reac-
tions to penicillin is uncertain except for fatal anaphylactic
reactions, which occur more frequently among atopic persons.
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305
FORMATION OF PENICILLIN ANTIGEN IN VIVO
O H H H
11 1 1 1 ~s~
R-C-N-C-I I (CH3)2
C-N CH-COOH
o
penicillin
ll
Isomerization
H SH
1 1
Nl IC = Cl Cl(CH3)2 _
R-C~ ~C~ N-CH-COOH
penicillenic acid
Protein
O H H H
R-C-N-C-C' ~C(CH3)2
C N CH-COOH
oil I
E-lysyl NH H
amide I
linkage ( I H2)4
-- --NH-CH C
11
o
panicilloyl - protein
MAJOR
ANTIGENIC
DETFRMINANT
MINOR
ANTIGENIC
DETERMINANTS
FIGURE 1. Major pathways of penicillin-protein interactions.
\
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306
There have been no detailed immunochemical studies of inter-
ac-tions of tetracycline with host proteins (Dewdney, 1977 ~ . The
protein reactivity of tetracyclines is generally considered to be
quite small. This fact alone is thought to account for the rarity
of hypersensitivity reactions to this class of antibiotics.
Individual Susceptibility
Recent studies by my laboratory have indicated that not all
individuals possess the capacity to respond immunologically to
therapeutically administered penicillin, even if treated with
prolonged high dose therapy (Adkinson, 1977~. This suggests that
there may be genetic and/or metabolic restrictions on the ability
to develop hypersensitivity reactions to penicillin. The propor-
tion of the general population that may be susceptible to the
development of allergy to penicillin remains to be determined.
Dosage Requirements for Sensitization
From immunological studies of laboratory animals and humans
it is clear that the dose of any immunogenic substance required
for initiating an immune response is appreciably greater than
that required to elicit an allergic reaction of the type I variety.
The optimal immunizing dose and the minimal dose for eliciting an
acute allergic reaction may differ by several orders of magnitude.
Furthermore, evidence from studies of both laboratory animals and
humans suggests that low-dose immunization favors the production
of IgE antibody over IgG antibody in animals that are genetically
capable of mounting an IgE antibody response (Marsh, 1975~. Thus,
there is reason to suspect that there may be a potential for the
development of IgE-mediated hypersensitivity by chronic low dose
antigenic exposure. ~
~· ~· ~
However. for ingested antigens (as opposed
to inhaled, airborne antigens) this potential risk has not been
explored by studies in either laboratory animals or humans. Thus,
there are no data to indicate whether penicillin administered to
humans chronically at residue-level doses can elicit a penicillin-
specific immune response in a susceptible individual. Likewise,
data concerning the threshold sensitizing dose for orally adminis-
tered penicilloyl-protein complexes are not available either for
laborato ry animals or humans.
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307
CONDITIONS FOR PROVOCATION OF ALLERGY SYMPTOMS
In an individual who has been rendered allergic to penicillin
by prior therapeutic administration, what is the risk of provoking
allergic symptoms by penicillin residues in ingested foodstuffs?
As discussed above, the dose required to elicit an allergic reaction
would be expected to be considerably below that required to initiate
an immune response. The threshold dose for provoking an allergic
reaction depends upon the degree of allergic sensitivity of the
individual ingesting the antibiotic residues.
Clinical observations were made by Walzer and Siegel in 1956
(Siegel, 1959~. They passively sensitized skin sites on normal
subjects with serum drawn from patients with high reagin (IgE) titers
to penicillin. All serum donors had previously experienced immediate
allergic reactions following treatment with penicillin. Seventy-two
hours later the recipient subjects were fed measured amounts of
crystalline penicillin G. and the sensitized sites were observed for
the appearance of wheel and flare signs, which are indicative of
IgE-mediated skin reactions. In those studies, which were positive,
the oral threshold dose of penicillin required to produce a positive
skin test was 40 to 50 units. Administered intravenously, doses of
12.5 to 25 units were sufficient to produce a positive skin response.
Siegel (1959) and Bierlein (1956) have provided evidence that
the oral dose of penicillin required to activate a passively sensi-
tized skin site in a normal recipient is from 100 to 10,000 times
larger than that needed to induce a clinical reaction in the aller-
gic patient from whom the reaginic serum was drawn. If one assumes
a conservative ratio of 100:1, then the oral administration of as
little as 0.4 units of penicillin would be sufficient to elicit
allergic reactions in patients with severe IgE-mediated peni-
cillin allergy.
A number of reports document systemic reactions in sensitive
individuals who were skin-tested with less than 1 unit of penicillin
G. including one patient who developed systemic symptoms following
an intradermal test with 3 x 10 units of penicillin (Bierlein,
1956~. It is therefore clear that very small doses of penicillin,
administered orally or through the skin, are capable of eliciting
allergic reactions in some exquisitely sensitive patients. It is
doubtful that such small doses could elicit clinical symptoms in a
majority of penicillin-allergic patients. Whether chronic ingestion
of subthreshold doses can eventually result in symptoms is likewise
unknown.
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308
EVIDENCE OF ALLERGIC REACTIONS TO ANTIBIOTIC RESIDUES
Milk
The literature yields only a few documented cases of allergic
symptoms that are clearly related to the presence of antibiotic
residues in animal foodstuffs. Almost all of these reports deal
with penicillin-contaminated milk. In 1959 Siegel carefully re-
viewed the data on allergic reactions to penicillin in milk. He
noted that in a 1956 Food and Drug Administration (FDA) nationwide
survey of penicillin contamination of milk, 5.9Z of the samples
were found to be contaminated with penicillin. The degree of con-
tamination ranged from 0.003 to 0.55 units/ml of milk, averaging
0.032 units/ml (D. C. Grove, personal communication; Welch, 1957~.
Zimmerman (1957-1958) reported that urticaria following ingestion
of milk was a common occurrence among 52 penicillin-sensitive
patients. Unfortunately, these patients were not studied immuno-
logically, nor were the implicated milk samples analyzed for
penicillin content.
The best studied case of allergic reaction from penicillin
in milk was reported by Borrie and Barrett (1961) in Great
Britain. A 25-year-old woman suffered a moderately severe sub-
acute eczematous eruption, which was traceable to penicillin-
contaminated milk. Analysis revealed that some milk samples that
did not contain penicillin were still capable of provoking allergic
symptoms. The patient's symptoms were relieved, however, by addi-
tion of penicillinase to the milk she consumed at home. Attempts
at desensitization by the oral route were undertaken starting at
1 unit of penicillin per day. Desensitization had to be abandoned
because of recurrent symptoms of allergy. For this patient, who
possessed an intense IgE-mediated allergy to penicillin, less than
1 unit (<0.6 g) of penicillin per day was sufficient to provoke
allergic symptoms. The elimination of her symptoms by the addition
of penicillinase to her milk may be taken as evidence that preformed
penicilloyl-milk protein complexes were not a major contributor to
the elicitation of her allergic reactions.
Stricter governmental enforcement of FDA regulations concern-
ing penicillin-contaminated milk has reduced considerably the
occult intake of penicillin by the general population over the past
two decades. By the mid-1960's the prevalence of penicillin-adult
~ (Huber, 1971b).
recently as 1969, Wicher et al. reported an acute allergic reac
tion in a highly penicillin-sensitive patient who had ingested
commercially available milk containing penicillin at approximately
10 units/ml.
orated milk in the United States had dropped to 0.5%
As
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309
Current FDA regulations prohibit measurable penicillin resi-
dues in milk offered for sale in the United States. Virtually all
penicillin contamination of milk products can be traced to the
therapeutic use of antibiotics in livestock and not to the use of
animal feeds containing subtherapeutic doses of penicillin. Thus,
the existence of allergies in humans that are attributable to
penicillin-contaminated milk can be considered irrelevant to the
substantive issue before the committee, namely, the health hazards
of subtherapeutic doses of antibiotics. However, these cases of
allergy induced by penicillin-contaminated milk provide useful in-
formation regarding minimal threshold doses required for provoking
allergic symptoms in highly sensitive patients.
Nonmilk Foodstuffs
A single case report from the Federal Republic of Germany
(Tscheuschner, 1972) documents acute angioedem~ and pruritus in
a penicillin-allergic patient who ingested freshly processed meat
from a pig that had been given a therapeutic injection of peni-
cillin 3 days prior to slaughter. Analysis of the ground pork
revealed a penicillin content of between 0.3 and 0.45 units/g of
meat. Since the patient noted symptoms after the first bite of
the ground pork, the minimum allergenic dose for this patient was
likely to have been less than 10 units of penicillin.
In France, Cany (1977) reported five cases of urticarial
reactions apparently induced by ingestion of food contaminated
with antibiotics. Unfortunately, the antibiotic residue contained
in the foodstuffs was not determined nor was the antibiotic sensi-
tivity of the patients confirmed immunologically. Nevertheless,
taken together, these descriptive case summaries raise the possi-
bility that antibiotic-contaminated foodstuffs may be responsible
for triggering allergic reactions more frequently than is generally
appreciated. Additional study of antibiotic residues in meat pro-
ducts produced in France would be helpful in further evaluations.
The literature contains no other documented cases of allergic
reactions attributable to residual antibiotics in animal tissues
other than milk.
LEVEL OF ANTIBIOTIC RESIDUES IN NONMILK FOODSTUFFS
T _
Penicillins have a relatively short half-life and are rapidly
eliminated from mammalian tissues after discontinuation of therapy.
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310
Tetracyclines are excreted fairly rapidly in urine but may require
4 to 5 days to disappear from soft tissues. Moreover, they have
a high affinity for bones and teeth. Messersmith et al. (1967)
demonstrated that pigs fed up to five times the usual recommended
concentration of penicillin in their feed (50 g of penicillin/
ton) continuously for 14 weeks had undetectable (<0.025 units
penicillin/g) penicillin residues in edible tissues within 0, 5,
and 7 days after withdrawal. In the same study, residues in pigs
fed up to 500 g of chlortetracycline/ton continuously for 14 weeks
were less than l ppm in all tissues in all sampling periods.
In 1970 Huber (1971b) studied the prevalence of antibacterial
drug residues in more than 5,000 animals at the time of slaughter.
Tissues, urine, and/or feces were collected from swine, sheep,
cattle, and poultry. Antibiotic residues ranged from a low of 9%
in beef cattle to a high of 27% in swine. Tetracycline residues
were found more frequently than were penicillin residues. This
and similar surveys (Dean et al., 1964) indicate that exposure to
antibiotic residues in foodstuffs by the general public has been
appreciable.
In view of the elimination studies by Messersmith et al.
(1967) and others (Huber, 1971a), the widespread antibiotic resi-
dues in edible meats as late as 1970 suggest that antibiotics were
used frequently in therapeutic doses and/or that required periods
for withdrawal from antibiotic-enriched feeds were being widely
ignored. More recent surveys have reported that penicillin residues
were found infrequently in edible meats except when the animals had
received injections of penicillins (Food and Drug Administration,
1978~. No tetracycline residues were detected among thousands of
meat samples analyzed in 1976 (Food and Drug Administration, 1978~.
In the United States the impact of these tissue residues on
human allergy may be mitigated somewhat by the fact that most
edible meats are cooked prior to consumption. Chlortetracycline
is changed by cooking into isochlortetracycline, a compound without
known biological activity (Shirk et al., 1956-1957~. Similarly,
the antibacterial activity of penicillin (and presumably its aller-
genic potential) is significantly reduced by heating (Shahani et
al., 1956~.
RISK ASSESSMENT
In view of the paucity of clinical, experimental, and epidem-
iological data, precise estimates of the risk of acquiring or mani-
festing allergic disease as a result of antibiotic residues in human
OCR for page 311
311
foodstuffs are impossible to derive. Nevertheless, several ob-
servations can be made in an attempt to set the potential human
health risks in perspective.
First, it seems highly unlikely that a sizable proportion
of those individuals ingesting foodstuffs containing trace
quantities of antibiotic residues will become sensitized to a
clinically significant degree. This assertion is based on
three facts:
· There is no evidence that such primary sensitization
occurred, even after ingestion of penicillin-contaminated milk.
Of course this does not prove that sensitization does not or
cannot occur, but merely that clinically apparent cases are
very rare or nonexistent.
· In this age of antibiotics, exposure to penicillin (and
other antibiotics) in therapeutic doses is very common, and the
prevalence of prior therapeutic exposure to antibiotics among
the adult population is appreciable. Thus, an individual is at
many orders of magnitude greater risk of becoming sensitized to
penicillin after treatment with a prescribed course of antibio-
tic than after ingestion of antibiotic residues in food. This
supposition reflects the frequency of antibiotic prescription.
~ Moreover, a greater rate of sensitization is to be ex-
pected from high (therapeutic) doses of antibiotics than from
the low-level exposures from foodstuffs. However, we know
virtually nothing about the immunogenicity of chronic low-dose
administration of penicillins and tetracyclines in human popu-
lations. Clearly, such studies would be useful in defining
further the risk potential for antibiotic sensitization by low
level exposure.
Of greater potential concern for human health is the
potential provocation of an allergic reaction in a previously
sensitized individual by ingestion of antibiotic residues. Here
again the literature contains only a sparse number of references
to allergic reactions that are traceable to antibiotic residues
in foods. Almost all of the cases reported have to do with
penicillin-contaminated milk, a moot issue from a regulatory point
of view, although there is certainly reason to continue monitor-
ing compliance to existing regulations.
The case reports dealing with sensitivity reactions to peni-
cillin-contaminated milk have led us to appreciate that very small
OCR for page 312
312
quantities of antibiotics are required to elicit clinically
significant allergic reactions in very sensitive individuals.
Apparently, some exquisitely sensitive individuals can experi-
ence adverse reactions to levels of penicillin that are unde-
tectable with standard assay methods. Judging from the rarity
of such cases, however, it is not unreasonable to conclude that
either most penicillin-allergic patients are not adversely
affected by penicillin residues in contaminated milk and/or
milk supplies are not frequently contaminated with penicillin
residues. The second conclusion is demons/ratably true. The
first conclusion is also likely to be correct since there has
been little evidence that widespread contamination has resulted
in a flurry of allergic problems, even during the early 1950's
when the prevalence of contamination of milk by penicillin was
7% to 15% in the United States.
Using the conservative estimate that the incidence of peni-
cilloyl IgE antibody in the general population is 1 in 50,000
and the assumption that 1% of penicillin-sensitive patients may
have ingested penicillin-contaminated milk over 1 year in the
early 1950's, one could expect an appreciable number of milk-
induced allergic reactions if the contaminated milk supplies were
capable of eliciting allergic reactions in an appreciable number
of sensitive individuals.
This analytical approach leads one to the tentative conclu-
sion that antibiotic-contaminated foodstuffs can provoke allergic
reactions in highly sensitive individuals, but these reactions
appear to occur only rarely.
Thus, the admittedly sparse data indicate that there appears
to be no reason to implicate antibiotic residues in animal foods
as a significant source of allergic disease, either potential or
actual, for the public at large.
CONCLUSIONS AND RECOMMENDATIONS
Based upon the above analysis' the following conclusions
appear warranted.
(1) There is little reason to believe that foodstuffs ob-
tained from animals fattened with antibiotic-supplemented
feeds impose a significant risk to human health by con-
tributing to antibiotic-induced allergic reactions.
OCR for page 313
313
(2) Data are currently lacking with regard to the clini-
cal consequences of oral administration of antibiotic
residues to patients with various degrees of provable
allergic sensitivity and the capacity of antibiotic
residues to engender a specific Immune response in a
genetically susceptible individual who ingests them
chronically in low doses.
The following investigations could be undertaken to provide
more definitive information on this question:
~ A study of the content of penicilloyl-protein complex
in edible tissues from animals who have been fed subtherapeutic
amounts of penicillin in their feed. Since the penicilloyl-pro-
tein complex may have a much longer half-life than does the free
penicillin molecule and since penicilloyl protein conjugates are
much more immunogenic than free penicillin, such a study would
provide needed information on the presence or absence of a poten-
tially Important Immunogenic residue, which until now has been
ignored.
Epidemiological studies of the incidence of penicillin
antibodies among populations frequently ingesting foods with peni-
cillin residues versus similar populations not regularly consuming
such antibiotic residues. Careful attention would have to be given
to matching the exposure to therapeutically administered penicillin
in both groups. Ideally, this study might be best conducted among
individuals who can provide documentation that they have never re-
ceived penicillin therapeutically.
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314
REFERENCES
Adkinson, N. F., Jr. 1977. Quantitative studies of the IgE and
IgG immune response to penicillin administration in man. Ann.
Allergy 39:73 (Abstract).
Adkinson, N. F., Jr., W. L. Thompson, W. C. Maddrey, and L. M.
Lichtenstein. 1971. Routine use of penicillin skin testing
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Almeyda, J., and A. Levantine. 1972. Drug reactions XIX. Adverse
cutaneous reactions to the penicillins--ampicillin rashes. Br.
J. Dermatol. 87:293-297.
Bierlein, K. J. 1956. Repeated anaphylactic reactions in a patient
highly sensitized to penicillin. A case report. Ann. Allergy
14 35~4 0e
Bierman, C. W., W. E. Pierson, S. J. Zeitz, L. S. Hoffman, and P. P.
VanArsdel, Jr. 1972. Reactions associated with ampicillin
therapy. J. Am. Med. Assoc. 220:1098-1100.
Borrie, P., and J. Barrett. 1961. Dermatitis caused by penicillin
in bulked milk supplies. Br. Med. J. 2:1267.
Cany, J. 1977. [In French; English summary.] One source clandes-
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Dear, D., J. K. Bennett, and E. L. Breazeale. 1964. Residual anti-
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Dewdney, J. M. 1977. Immunology of the antibiotics. Pp. 74-225 in
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Feinberg, S. M. 1961. Allergy from therapeutic products. Incidence,
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-Green, G. R., A. H. Rosenblum, and L. C. Sweet. 1977. Evaluation of
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Levine, B. B. 1966. Immunochemical mechanisms of drug allergy.
Annul Rev. Med. 17:23-38.
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Shirk, R. J., A. R. Whitehall, and L. R. Hines. 1956-1957. A degra-
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Annul 312-326.
Representative terms from entire chapter:
antibiotic residues
